Alzheimer & Parkinson

Protein fibril surfaces tend to generate toxic oligomers catalytically. To date, efforts to study the accelerated aggregation steps involved with Alzheimer's disease-linked amyloid-β (Aβ)-42 proteins on fibril surfaces have mainly relied on fluorophore-based analytics. Here, we visualize rare secondary nucleation events on the surface of Aβ-42 fibrils from embryonic to endpoint stages using liquid-based atomic force microscopy. Nanoscale imaging supported by atomic-scale molecular simulations...

Aging is an intricate process involving interactions among multiple factors, which is one of the main risks for chronic diseases, including Alzheimer's disease (AD). As a member of cysteine protease, cathepsin S (CTSS) has been implicated in inflammation across various diseases. Here, we investigated the role of neuronal CTSS in aging and AD started by examining CTSS expression in hippocampus neurons of aging mice and identified a significant increase, which was negatively correlated with...

Genome-scale metabolic models (GEMs) cover the entire list of metabolic genes in an organism and associated reactions, in a tissue/condition non-specific manner. RNA-seq provides crucial information to make the GEMs condition-specific. Integrative Metabolic Analysis Tool (iMAT) and Integrative Network Inference for Tissues (INIT) are the two most popular algorithms to create condition-specific GEMs from human transcriptome data. The normalization method of choice for raw RNA-seq count data...

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Parkinson's disease is a heterogenous neurodegenerative disorder with a wide variety of motor and non-motor symptoms. This study used resting-state fMRI to identify the neural substrates of PD and explore the acute neural response to acupuncture stimulation in 74 participants (50 patients with PD and 24 healthy controls). All participants with PD were evaluated for the severity of symptoms using the Unified Parkinson's Disease Rating Scale and Balance Master. The z-transformed fractional...

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The ability to generate visceral sensory neurons (VSN) from induced pluripotent stem (iPS) cells may help to gain insights into how the gut-nerve-brain axis is involved in neurological disorders. We established a protocol to differentiate human iPS-cell-derived visceral sensory ganglion organoids (VSGOs). VSGOs exhibit canonical VSN markers, and single-cell RNA sequencing revealed heterogenous molecular signatures and developmental trajectories of VSGOs aligned with native VSN. We integrated...

Emerged evidence indicated that stimulating hippocampal neurogenesis is a potential strategy for restoring cognition in AD. Mitogen-activated protein kinases (MAPKs) play an essential role in neurogenesis. Meanwhile, the enzymatic power of the phosphatases is much greater than that of kinases. Dual-specificity phosphatase 16 (DUSP16), known to as a phosphatase negatively regulate MAPKs, may be implicated in neural differentiation. Nevertheless, the effect of DUSP16 on cognitive disorders by...

Subcortical brain structures are involved in developmental, psychiatric and neurological disorders. Here we performed genome-wide association studies meta-analyses of intracranial and nine subcortical brain volumes (brainstem, caudate nucleus, putamen, hippocampus, globus pallidus, thalamus, nucleus accumbens, amygdala and the ventral diencephalon) in 74,898 participants of European ancestry. We identified 254 independent loci associated with these brain volumes, explaining up to 35% of...

Computer-vision and machine-learning (ML) approaches are being developed to provide scalable, unbiased, and sensitive methods to assess mouse behavior. Here, we used the ML-based variational animal motion embedding (VAME) segmentation platform to assess spontaneous behavior in humanized App knockin and transgenic APP models of Alzheimer's disease (AD) and to test the role of AD-related neuroinflammation in these behavioral manifestations. We found marked alterations in spontaneous behavior in...

Synucleinopathies, including Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy, are triggered by α-synuclein aggregation, triggering progressive neurodegeneration. However, the intracellular α-synuclein aggregation mechanism remains unclear. Herein, we demonstrate that RNA G-quadruplex assembly forms scaffolds for α-synuclein aggregation, contributing to neurodegeneration. Purified α-synuclein binds RNA G-quadruplexes directly through the N terminus. RNA G-quadruplexes...

Yamanaka factors (YFs) can reverse some aging features in mammalian tissues, but their effects on the brain remain largely unexplored. Here, we induced YFs in the mouse brain in a controlled spatiotemporal manner in two different scenarios: brain development and adult stages in the context of neurodegeneration. Embryonic induction of YFs perturbed cell identity of both progenitors and neurons, but transient and low-level expression is tolerated by these cells. Under these conditions, YF...

Bis(monoacylglycero)phosphate (BMP) is an abundant lysosomal phospholipid required for degradation of lipids, particularly gangliosides. Alterations in BMP levels are associated with neurodegenerative diseases. Unlike typical glycerophospholipids, lysosomal BMP has two chiral glycerol carbons in the S (rather than the R) stereo-conformation, protecting it from lysosomal degradation. How this unusual and yet crucial S,S-stereochemistry is achieved is unknown. Here, we report that phospholipases...

Sirtuin 1 (SIRT1), an NAD+-dependent deacetylase, has emerged as a key regulator of cellular processes linked to ageing and neurodegeneration. SIRT1 modulates various signalling pathways, including those involved in autophagy, oxidative stress, and mitochondrial function, which are critical in the pathogenesis of neurodegenerative diseases. This review explores the therapeutic potential of SIRT1 in several neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD),...

Retrotransposable elements (RTEs) are common mobile genetic elements comprising ∼42% of the human genome. RTEs play critical roles in gene regulation and function, but how they are specifically involved in complex diseases is largely unknown. Here, we investigate the cellular heterogeneity of RTEs using 12 single-cell transcriptome profiles covering three neurodegenerative diseases, Alzheimer's disease (AD), Parkinson's disease, and multiple sclerosis. We identify cell type marker RTEs in...

Maintaining mitochondrial homeostasis is crucial for cell survival and organismal health, as evidenced by the links between mitochondrial dysfunction and various diseases, including Alzheimer's disease (AD). Here, we report that lncMtDloop, a non-coding RNA of unknown function encoded within the D-loop region of the mitochondrial genome, maintains mitochondrial RNA levels and function with age. lncMtDloop expression is decreased in the brains of both human AD patients and 3xTg AD mouse models....

Stem cell therapies for Parkinson's disease are at an exciting time of development, and several clinical trials have recently been initiated. Human pluripotent stem cells are differentiated into transplantable dopamine (DA) progenitors which are proliferative at the time of grafting and undergo terminal differentiation and maturation in vivo. While the progenitors are homogeneous at the time of transplantation, they give rise to heterogeneous grafts composed not only of therapeutic DA neurons...

Adults with prediabetes are at risk for Alzheimer's Disease and Related Dementia (ADRD). While exercise may lower ADRD risk, the exact mechanism is unclear. We tested the hypothesis that short-term exercise would raise neuronal insulin signaling and pro-BDNF in neuronal extracellular vesicles (nEVs) in prediabetes. Twenty-one older adults (18F, 60.0 ± 8.6 yrs.; BMI: 33.5 ± 1.1 kg/m²) with prediabetes (ADA criteria; 75 g OGTT) were randomized to 12 supervised work-matched continuous (n = 13, 70%...